1. Field of the Invention
The present invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. The present invention further relates to methods of preparing such inhibitors, compositions which contain such an inhibitor, and methods of treating and/or preventing certain diseases by administering an effective amount of such an inhibitor.
2. Discussion of the Background
The cyclic nucleotide specific phosphodiesterases (PDEs) comprise a family with eleven isoenzymes, known at present, that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers within cells and as messengers, carry impulses from cell surface receptors having bound various hormones and neurotransmitters. PDEs regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides resulting in termination of their messenger role.
The isoenzymes can be grouped according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds.
PDE4 is cAMP specific and its inhibition causes airway relaxation, anti-inflammatory, enhanced cognition, and antidepressant activity.
Therefore inhibitors of PDE4 isoenzymes are therapeutic agents which may be useful in treating diseases involving inflammation, such as asthma or arthritis, or diseases of the central nervous such as cognitive decline or memory loss.
Various chemical classes of PDE4 inhibitors are known.
In particular, PDE4 inhibitors belonging to the tertiary amine class have been described in WO 2005/061458 and WO 2006/135828.
However, it is generally known that compounds having IC50 values higher that 1000 nM may show an unsatisfactory therapeutic activity.
As a consequence, the activity of the known PDE4 inhibitors, in particular of those belonging to the tertiary amine class, still requires improvement.
Thus, there remains a need for compounds belonging to the tertiary amine class, whose activity is improved compared to the known PDE4 inhibitors.